Skip to main content
Article thumbnail
Location of Repository

Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers

By Vincenzo Bronte, Tihana Kasic, Giorgia Gri, Keti Gallana, Giovanna Borsellino, Ilaria Marigo, Luca Battistini, Massimo Iafrate, Tommaso Prayer-Galetti, Francesco Pagano and Antonella Viola


Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy

Topics: Article
Publisher: The Rockefeller University Press
OAI identifier:
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles


    1. (2001). 1268 and the future: cellular immunotherapy for cancer.
    2. (1991). A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells.
    3. (2003). Adoptive-cell-transfer therapy for the treatment of patients with cancer.
    4. (1987). Antigen receptor-regulated exocytosis in cytotoxic T lymphocytes.
    5. (2002). Arginase activity is inhibited by L-NAME, both in vitro and in vivo.
    6. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res.
    7. (2004). Arginases I and II: do their functions overlap?
    8. (1998). Arginine metabolism: nitric oxide and beyond.
    9. (2003). Biological selectivity and functional aspects of protein tyrosine nitration.
    10. (2002). Blocking NO synthesis: how, where and why?
    11. (2002). Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going?
    12. (2004). Cancer immunotherapy: moving beyond current vaccines.
    13. (2003). Cancer vaccines: between the idea and the reality.
    14. (2000). Cancer-induced defective cytotoxic T lymphocyte effector function: another mechanism how antigenic tumors escape immune-mediated killing.
    15. (2001). CD8 tumor-infiltrating lymphocytes are primed for Fas-mediated activation-induced cell death but are not apoptotic in situ.
    16. (2001). CD8( ) tumor-infiltrating T cells are deficient in perforinmediated cytolytic activity due to defective microtubule-organizing center mobilization and lytic granule exocytosis.
    17. (1999). Characteristics of nonmalignant and malignant human prostate in organ culture.
    18. (2001). Classical and slow-binding inhibitors of human type II arginase.
    19. (1997). Cytotoxicity and apoptosis in human renal allografts: identification, distribution, and quantitation of cells with a cytotoxic granule protein GMP-17 (TIA-1) and cells with fragmented nuclear DNA.
    20. (2003). Delivering the kiss of death.
    21. (1999). Denitration of peroxynitrite-treated proteins by ‘protein nitratases’ from rat brain and heart.
    22. (2004). Dynamics of protein nitration in cells and mitochondria.
    23. (2004). Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance.
    24. (2000). Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance.
    25. (2003). Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase.
    26. (2004). Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes.
    27. (2003). Expression of inducible nitric oxide synthase in paired neoplastic and non-neoplastic primary prostate cell cultures and prostatectomy specimen.
    28. (1996). Growth of tumorinfiltrating lymphocytes from human solid cancers: summary of a 5-year experience.
    29. (1994). Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma.
    30. (2003). IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice.
    31. (1998). Immune cells in the tumor microenvironment. Mechanisms responsible for functional and signaling defects.
    32. (2001). Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells.
    33. (2003). Immunosensitization of resistant human tumor cells to cytotoxicity by tumor infiltrating lymphocytes.
    34. (2001). In vivo and in vitro apoptosis of human thymocytes are associated with nitrotyrosine formation.
    35. (2001). Inducible nitric oxide synthase (iNOS) expression and its prognostic value in prostate cancer. Anticancer Res.
    36. (1998). Inducible nitric-oxide synthase generates superoxide from the reductase domain.
    37. (2004). Inflammation and necrosis promote tumour growth.
    38. Intratumoral CD8 T lymphocytes as a prognostic factor of survival in endometrial carcinoma.
    39. (2003). Intratumoral T cells, recurrence, and survival in epithelial ovarian
    40. L-arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol.
    41. (2001). Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res.
    42. (2002). Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol.
    43. (2001). Nitric oxide and the immune response.
    44. (2000). Nitric oxide upregulates expression of DNA-PKcs to protect cells from DNA-damaging anti-tumour agents.
    45. (2003). NO-dependent protein nitration: a cell signaling event or an oxidative inflammatory response? Trends Biochem.
    46. Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model.
    47. (1999). Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death.
    48. (1997). Peroxynitrite rapidly permeates phospholipid membranes.
    49. (1999). Peroxynitrite: reactive, invasive and enigmatic.
    50. (2001). Possible implications of arginase and diamine oxidase in prostatic carcinoma. Cancer Detect.
    51. (2002). Prospective molecular profiling of melanoma metastases suggests classifiers of immune responsiveness. Cancer Res.
    52. (2001). Proteomic method identifies proteins nitrated in vivo during inflammatory challenge.
    53. Roles of nitric oxide in tumor growth.
    54. selective oxygen-regulated protein tyrosine denitration and nitration in mitochondria.
    55. (1999). Signaling defects in T lymphocytes of patients with malignancy.
    56. (1997). Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages.
    57. (2003). T-cell responses of vaccinated cancer patients.
    58. (2004). TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response.
    59. (2003). The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal.
    60. (2002). The role of nitric oxide in cancer. Cell Res.
    61. (2002). Tumor-specific shared antigenic peptides recognized by human T cells.
    62. (1999). Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.